SummaryWe report genome-wide ancient DNA from 49 individuals forming four parallel time transects in Belize, Brazil, the Central Andes, and the Southern Cone, each dating to at least ∼9,000 years ago. The common ancestral population radiated rapidly from just one of the two early branches that contributed to Native Americans today. We document two previously unappreciated streams of gene flow between North and South America. One affected the Central Andes by ∼4,200 years ago, while the other explains an affinity between the oldest North American genome associated with the Clovis culture and the oldest Central and South Americans from Chile, Brazil, and Belize. However, this was not the primary source for later South Americans, as the other ancient individuals derive from lineages without specific affinity to the Clovis-associated genome, suggesting a population replacement that began at least 9,000 years ago and was followed by substantial population continuity in multiple regions.

Currently, no approved therapeutics exist to treat or prevent infections induced by Ebola viruses, and recent events have demonstrated an urgent need for rapid discovery of new treatments. Repurposing approved drugs for emerging infections remains a critical resource for potential antiviral therapies. We tested ~2600 approved drugs and molecular probes in an in vitro infection assay using the type species, Zaire ebolavirus. Selective antiviral activity was found for 80 U.S. Food and Drug Administration–approved drugs spanning multiple mechanistic classes, including selective estrogen receptor modulators, antihistamines, calcium channel blockers, and antidepressants. Results using an in vivo murine Ebola virus infection model confirmed the protective ability of several drugs, such as bepridil and sertraline. Viral entry assays indicated that most of these antiviral drugs block a late stage of viral entry. By nature of their approved status, these drugs have the potential to be rapidly advanced to clinical settings and used as therapeutic countermeasures for Ebola virus infections.

The highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) cause significant morbidity and morality. There is currently no approved therapeutic for highly pathogenic coronaviruses, even as MERS-CoV is spreading throughout the Middle East. We previously screened a library of FDA-approved drugs for inhibitors of coronavirus replication in which we identified Abelson (Abl) kinase inhibitors, including the anticancer drug imatinib, as inhibitors of both SARS-CoV and MERS-CoV in vitro. Here we show that the anti-CoV activity of imatinib occurs at the early stages of infection, after internalization and endosomal trafficking, by inhibiting fusion of the virions at the endosomal membrane. We specifically identified the imatinib target, Abelson tyrosine-protein kinase 2 (Abl2), as required for efficient SARS-CoV and MERS-CoV replication in vitro. These data demonstrate that specific approved drugs can be characterized in vitro for their anticoronavirus activity and used to identify host proteins required for coronavirus replication. This type of study is an important step in the repurposing of approved drugs for treatment of emerging coronaviruses. T he severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses (CoVs) are two highly pathogenic viruses that infect humans. These viruses undergo a distinct replication cycle, involving virion entry, RNA genome replication and transcription of viral mRNAs, protein translation, virion assembly in the endoplasmic reticulum (ER)-Golgi intermediate complex, and egress by exocytosis of assembled virions (reviewed in reference 1). Coronavirus entry can be further subdivided into virion binding, receptor-mediated endocytosis, intracellular trafficking, and protease-dependent cleavage of spike (S) protein, leading to fusion of the virion membrane to the endosomal membrane. The SARS-CoV virion is endocytosed following S binding to angiotensin-converting enzyme 2 (ACE2) and trafficking to the late endosome, where the virion membrane fuses with the endosomal membrane in a cathepsin L-dependent manner (2). The MERS-CoV virion is endocytosed following S binding to dipeptidyl peptidase 4 (DPP4) and trafficking to the early endosome, where the virion membrane fuses with the endosomal membrane in a furin-dependent manner (3). IMPORTANCE Both SARS-CoV and MERS-The outbreaks of SARS-CoV and MERS-CoV highlight the need to find treatments for these and potential future coronavirus outbreaks. The drug development process from novel compound to approved drug generally takes over 10 years, making it impractical to develop novel anticoronavirus drugs once an outbreak begins. For SARS-CoV, drugs that inhibit the viral protease (4-7), replicase (8-10), or helicase (10, 11) in vitro have been identified;

As the medical education community celebrates the 100th anniversary of the seminal Flexner Report, medical education is once again experiencing significant pressure to transform. Multiple reports from many of medicine's specialties and external stakeholders highlight the inadequacies of current training models to prepare a physician workforce to meet the needs of an increasingly diverse and aging population. This transformation, driven by competency-based medical education (CBME) principles that emphasize the outcomes, will require more effective evaluation and feedback by faculty.Substantial evidence suggests, however, that current faculty are insufficiently prepared for this task across both the traditional competencies of medical knowledge, clinical skills, and professionalism and the newer competencies of evidence-based practice, quality improvement, interdisciplinary teamwork, and systems. The implication of these observations is that the medical education enterprise urgently needs an international initiative of faculty development around CBME and assessment. In this article, the authors outline the current challenges and provide suggestions on where faculty development efforts should be focused and how such an initiative might be accomplished. The public, patients, and trainees need the medical education enterprise to improve training and outcomes now.